The HIV-associated emotional and motivational disorders (HEMDs) include severe depression, serious apathy, persistent sadness, and decreased appetite. These HEMDs cause non-compliance with treatment, an increase in high-risk behaviors, and suicidal death, and thus substantially impact the already-afflicted life of AIDS-patients. A gap in our knowledge that prevents us from developing effective treatments for HEMDs is that we do not know the neuronal mechanisms that mediate HEMDs. To address this knowledge gap, we will target the nucleus accumbens (NAc) because this site is one of the central targets for HIV-infection, and malfunction of the NAc results in a variety of emotional and motivational disorders similar to HEMDs. Our longterm goal is to identify the key molecular substrates in the NAc, the manipulation of which can prevent or ameliorate HEMDs. Our promising preliminary results suggest that the NR2A-containing N-methyl-Daspartate receptor (NMDAR) and its coupled signaling may be such key molecular substrates that can protect NAc neurons from the HIV insult. As an initial step toward our long-term goal, the objective of this R21 application is to 1) establish the relationship between HIV-induced NAc neurodegeneration and motivational deficits; and 2) determine the potential neuroprotective effect of manipulating the NMDAR-pathway in HIVinduced NAc neurodegeneration in a Tat-expressing mouse line. Tat is a neurotoxic protein released by HIV. Our central hypothesis is that Tat-induced NAc neurodegeneration is positively correlated with compromised motivational behaviors, and that activation of NR2A-containing NMDARs protects Tat-induced neurodegeneration of NAc neurons. Given that several NMDAR-based compounds have already been used in clinical trials, our proposed research may have immediate clinical impact on the treatment of HEMDs. Thus, our studies are highly relevant to the mission of the NIH to develop fundamental knowledge that will potentially help to reduce the burden of human disability. Guided by our promising preliminary data, our objective will be achieved by pursuing two specific aims: 1) Define the role of Tat-induced NAc neurodegeneration in HEMDs; and 2) Define the neuroprotective role of the NR2A-pathway in Tat-induced NAc neurodegeneration. Under both aims, we will use a line of transgenic mice in which expression of Tat can be temporally and quantitatively controlled. The proposed work is innovative because it will establish the first HEMD model linking the HIV-induced cellular and molecular changes to a detectable behavioral output. The proposed work also broadly and positively impacts the NeuroAIDS field as a whole in that the advanced behavioral and electrophysiological paradigms to be established are broadly applicable to studies of other HIV-induced neurodegenerative mechanisms. Furthermore, the NMDAR-based mechanism to be examined may have a general neuroprotective effect in other HIV-induced pathological conditions. PUBLIC HEALTH RELEVANCE: A set of devastating psychiatric symptoms, such as severe depression, profound apathy, persistent sadness, and decreased appetite, is often concurrent with Acquired Immunodeficiency Syndrome (AIDS) in Human Immunodeficiency Virus (HIV)-infected patients. This application will define the role of a subtype of NMDA receptors in the rescue of HIV-associated emotional and motivational disorders. The proposed research is highly relevant to public health, because the outcomes of our work may introduce a novel clinical approach to treat HIV-induced emotional and motivational disorders.